Persistent Methicillin-Susceptible Bacteremia Rapidly Cleared with Cefazolin and Ertapenem Combination Therapy in a Patient with COVID-19

Methicillin-susceptible Staphylococcus aureus (MSSA) bloodstream infections (BSIs) are associated with significant morbidity and mortality. MSSA BSIs can rapidly disseminate, resulting in deep-seated infections, prolonged durations of bacteremia, and further metastases. Recently, cefazolin and ertapenem combination therapy has emerged as a potential therapeutic strategy to sterilize the blood in patients with persistent MSSA bacteremia. Here, we present a patient with COVID-19 pneumonia and concomitant MSSA BSI achieving blood culture sterilization within 24 hours of cefazolin and ertapenem combination therapy initiation following 11 days of positive blood cultures.


Introduction
Staphylococcus aureus is a leading cause of bloodstream infections (BSIs), with an annual incidence in the United States of approximately 30 cases per 100,000 person-years [1]. S. aureus BSI is associated with high morbidity and mortality, with 30-day all-cause mortality rates ranging from 20 to 30% [2,3]. In recent years, MSSA has once again emerged as the predominant cause of staphylococcal bacteremia [4]. us, optimizing treatment strategies for MSSA BSI is paramount. e treatment of choice for MSSA BSI is source control along with an antistaphylococcal penicillin, such as oxacillin or nafcillin or cefazolin [5]. Persistent bacteremia, defined anywhere from 2 to 7 days of positive blood cultures despite appropriate antibiotic therapy, is associated with worse outcomes and higher mortality compared to bacteremias that clear rapidly [6,7]. Unfortunately, modifications to antibacterial therapy, including the addition of rifampin [8] and daptomycin [9], have not proven beneficial in patients with MSSA BSI. e addition of gentamicin has been used historically but is no longer recommended due to an unacceptable risk of nephrotoxicity when combined with antistaphylococcal penicillins [5].
Recently, combination therapy with cefazolin and ertapenem has emerged as a possible rescue therapy in patients with persistent MSSA BSI. e combination demonstrated synergy both in vitro and in vivo in a murine skin infection model [10]. In a small case series, combination therapy was found to sterilize blood cultures within 24 hours of initiation in 8 of 9 patients with daily blood culture samples [11]. In another case report of a neonate with eight days of positive blood cultures, escalating to cefazolin and ertapenem preceded negative blood cultures 30 hours later [12]. More data, however, about clinical outcomes are needed. Here, we describe a case in which blood culture sterilization was observed within 24 hours of initiation of cefazolin and ertapenem combination therapy after 11 days of persistent bacteremia on oxacillin in a patient with MSSA BSI and COVID-19.

Case Description
A 45-year-old male with a past medical history significant for obstructive sleep apnea, congenital club foot status post corrective surgery years prior, and recently diagnosed COVID-19 (10 days prior to admission) presented to the emergency department with increasing weakness, fatigue, and loss of appetite. e patient got tested for COVID-19 after his partner developed respiratory symptoms. Respiratory symptoms at home included cough, shortness of breath, and fevers. e patient also reported using his continuous positive airway pressure machine during the day for increased dyspnea. Additionally, he reported progressive right ankle pain and redness over the last week. On physical exam, the right ankle was warm and erythematous without gross effusion and was tender to palpation and passive range of motion. Initial vital signs were remarkable for a respiratory rate of 28 breaths/minute, heart rate of 116 beats/ minute, blood pressure of 184/96 mm·Hg, and a body mass index of 40 kg/m 2 . Complete metabolic panel revealed an elevated glucose of 462 mg/dL, blood urea nitrogen of 80 mg/dL, and serum creatinine of 5.40 mg/dL (estimated creatinine clearance 23 ml/min). Additional labs were remarkable for HgA1c of 7.2%, NT-proBNP of 867 pg/mL, CRP of 329.3 mg/dL, ESR of 103 mm/hr, lactate of 2.7 mmol/L, and a D-dimer of 4623 mcg/mL. Blood and urine cultures were sent. Chest X-ray showed bilateral patchy airspace and interstitial opacities, predominantly involving the periphery of the right lung. Right ankle/foot X-ray showed findings consistent with prior congenital foot surgery without osseous erosions or fractures. He received 1 L lactated ringers, 5 units of lispro, and a dose of intravenous vancomycin 1750 mg before transfer to the medical intensive care unit (MICU) for BiPAP.
Complete details of the hospital course are provided in Table 1.
e patient was initially started on intravenous dexamethasone and remdesivir in the MICU. Antimicrobial therapy was changed to oxacillin on day 2 following the detection of MSSA in initial blood cultures via Verigene Blood Culture Nucleic Acid Test. Infectious disease was consulted the following day in accordance with institutional practice for all patients with staphylococcal BSIs. An MRI performed on the right ankle revealed diffuse skin thickening and edema of foot and ankle without evidence of OM, large complex tibiotalar joint effusion with synovitis, and abscess along the flexor hallucis longus muscle (Figure 1), which was urgently debrided in the operating room. e following day, the patient was weaned from BiPAP back to CPAP at night only.
Despite initial source control and appropriate antimicrobial therapy, blood cultures remained positive. Echocardiographic imaging on days 2 and 7 did not reveal any valvular vegetations; yet, the patient remained persistently bacteremic despite therapy with intravenous oxacillin. On day 9 of admission, the patient was escalated to intravenous cefazolin and ertapenem combination therapy and dexamethasone was stopped with the completion of 10 doses. On the same day, an MRI spine revealed discitis/osteomyelitis of the cervical spine with associated epidural abscess ( Figure 2). e patient was taken for urgent debridement and C 3 to C 4 cervical fusion. Intraoperative spinal cultures grew MSSA. Repeat blood cultures within 24 hours of administration of cefazolin and ertapenem combination therapy finalized without growth. Follow-up cultures remained sterile through hospital discharge on day 19. e patient was discharged to a long-term acute care facility to complete 6 weeks of intravenous cefazolin and ertapenem from the first negative blood culture.

Discussion
MSSA bacteremia is a common BSI associated with significant morbidity and mortality [2,3]. Effective management includes source control and treatment with antistaphylococcal penicillin or cefazolin. Limited therapeutic options exist for recalcitrant MSSA BSIs not responding to standard therapy and source control.
Here, we report on a patient with newly diagnosed diabetes mellitus, COVID-19 pneumonia, and concomitant MSSA BSI not responding to the standard of care therapy with oxacillin and initial source control procedures. Following more than 10 days of persistent bacteremia, blood cultures were sterilized within 24 hours of administration of cefazolin and ertapenem combination therapy.
Cefazolin and ertapenem bind to different penicillinbinding proteins (PBPs), with ertapenem selectively targeting PBP1 and cefazolin predominantly binding to PBP2. [13][14][15] Such complementary binding affinities provide the theoretical pharmacodynamic foundation for utilizing these two agents in combination. A recent case series highlights the potential utility of cefazolin and ertapenem in combination as salvage therapy for persistent MSSA BSIs [11]. In this series, 8 of 11 patients achieved negative blood cultures within 24 hours of initiation of salvage therapy. Most patients in this series had deep-seated infections, including 6 with endocarditis and 2 with spinal osteomyelitis and epidural abscesses. Additionally, the authors noted synergy when testing the combination in vitro and in a rat model of endocarditis [11]. While the duration of S. aureus bacteremia has not been associated with 90-day mortality, it has been associated with other significant complications. ese include new metastatic foci of infection (often requiring surgical interventions), relapse of bacteremia, longer hospital stay, and complications due to longer hospital stay [7,16]. Together, these serve as a rationale for salvage therapy with combination antimicrobials in recalcitrant bacteremia.
Regarding the management of the patient's COVID-19 pneumonia, our patient initially received intravenous dexamethasone and remdesivir; however, the latter was held following the administration of a loading dose given the patient's acute renal failure. Dexamethasone was continued for a complete 10-day course in accordance with clinical treatment guidelines [17]; however, new initiation of corticosteroids in patients with staphylococcal BSIs without concomitant shock has been associated with increased allcause mortality at 28 and 90 days [18]. ese data highlight the need to critically weigh the risks and benefits of continued dexamethasone therapy in the setting of secondary infections in patients with COVID-19.
One final consideration is the timing of source control relative to the imitation of cefazolin and ertapenem combination therapy. As a case report, we cannot be certain of the causal link between the antibiotic change and the cessation of bacteremia, but the temporal proximity does raise this as a possibility. In addition, while an undrained epidural abscess could explain persistent fevers and symptoms, undrained collections are rarely the cause of continuous bacteremia (hence, our clinical use of continuous bacteremia as the sine qua non of endovascular infection). In total, this case suggests to us the possibility of an effect, and one worth reporting as a case study, in order to pique the interest of other clinicians or to contribute eventually to a case series, before undertaking a more rigorous study design.

Conclusion
Cefazolin and ertapenem combination therapy resulted in successful sterilization of blood cultures within 24 hours of administration in a patient previously bacteremic for more than 10 days despite optimal pharmacotherapy. e patient's MSSA BSI may have been aggravated by continued administration of dexamethasone for COVID-19. Clinicians should consider weighing the risks and benefits of dexamethasone administration in the setting of concomitant infections.

Consent
No written consent has been obtained from the patients as there are no patient identifiable data included in this case report/series.

Conflicts of Interest
e authors have no relevant conflicts of interest to disclose.